Genomes and Genes
ribosomal protein s6 kinases
Summary: A family of protein serine/threonine kinases which act as intracellular signalling intermediates. Ribosomal protein S6 kinases are activated through phosphorylation in response to a variety of HORMONES and INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS. Phosphorylation of RIBOSOMAL PROTEIN S6 by enzymes in this class results in increased expression of 5' top MRNAs. Although specific for RIBOSOMAL PROTEIN S6 members of this class of kinases can act on a number of substrates within the cell. The immunosuppressant SIROLIMUS inhibits the activation of ribosomal protein S6 kinases.
- Buck M. Targeting ribosomal S-6 kinase for the prevention and treatment of liver injury and liver fibrosis. Drug News Perspect. 2008;21:301-6 pubmed publisher..Thus, appropriate RSK inhibitors may be beneficial in the prevention and treatment of liver injury and liver fibrosis. These issues will be discussed in this review. ..
- Xue Q, Nagy J, Manseau E, Phung T, Dvorak H, Benjamin L. Rapamycin inhibition of the Akt/mTOR pathway blocks select stages of VEGF-A164-driven angiogenesis, in part by blocking S6Kinase. Arterioscler Thromb Vasc Biol. 2009;29:1172-8 pubmed publisher..Rapamycin decreased phosphorylation of both Akt and S6, suggesting that both the TORC1 and TORC2 pathways are impacted. Inhibition of S6K1 signaling downstream of mTOR is a major component of the antiangiogenesis action of rapamycin. ..
- Bielinski V, Mumby M. Functional analysis of the PP2A subfamily of protein phosphatases in regulating Drosophila S6 kinase. Exp Cell Res. 2007;313:3117-26 pubmed..These results indicate that PP2A, but not other members of this subfamily, is likely to be a major S6K phosphatase in intact cells and is consistent with an important role for this phosphatase in the TOR pathway. ..
- Dowling R, Topisirovic I, Alain T, Bidinosti M, Fonseca B, Petroulakis E, et al. mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science. 2010;328:1172-6 pubmed publisher..Thus, control of cell size and cell cycle progression appear to be independent in mammalian cells, whereas in lower eukaryotes, 4E-BPs influence both cell growth and proliferation. ..
- Weatherill D, Dyer J, Sossin W. Ribosomal protein S6 kinase is a critical downstream effector of the target of rapamycin complex 1 for long-term facilitation in Aplysia. J Biol Chem. 2010;285:12255-67 pubmed publisher..Thus, we demonstrate that S6K is an important downstream target of TORC1 in Aplysia and that it is necessary for 24-h LTF, but not for TORC1-mediated increases in somatic cap-dependent translation...
- Villanueva E, Munzberg H, Cota D, Leshan R, Kopp K, Ishida Takahashi R, et al. Complex regulation of mammalian target of rapamycin complex 1 in the basomedial hypothalamus by leptin and nutritional status. Endocrinology. 2009;150:4541-51 pubmed publisher..The regulation of mTORC1 in the basomedial hypothalamus thus varies by cell and stimulus type, as opposed to responding in a uniform manner to nutritional and hormonal perturbations. ..
- Castaneda T, Abplanalp W, Um S, Pfluger P, Schrott B, Brown K, et al. Metabolic control by S6 kinases depends on dietary lipids. PLoS ONE. 2012;7:e32631 pubmed publisher..Taken together, our results suggest that the metabolic functions of S6K in vivo play a key role as a molecular interface connecting dietary lipids to the endogenous control of energy metabolism. ..
- Qin Z, Hua Y, Liu W, Silbergleit R, He Y, Keep R, et al. Hyperbaric oxygen preconditioning activates ribosomal protein S6 kinases and reduces brain swelling after intracerebral hemorrhage. Acta Neurochir Suppl. 2008;102:317-20 pubmedNew protein synthesis is key to ischemic tolerance induced by preconditioning and ribosomal protein S6 kinases (p70 S6 K) are important enzymes in protein synthesis. Hyperbaric oxygen preconditioning (HBOP) reduces ischemic brain damage...
- Fraenkel M, Ketzinel Gilad M, Ariav Y, Pappo O, Karaca M, Castel J, et al. mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes. 2008;57:945-57 pubmed publisher..These findings emphasize the essential role of mTOR/S6K1 in orchestrating beta-cell adaptation to hyperglycemia in type 2 diabetes. It is likely that treatments based on mTOR inhibition will cause exacerbation of diabetes. ..
- Huang J, Manning B. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J. 2008;412:179-90 pubmed publisher..In the present review we focus on the molecular details of TSC1-TSC2 complex regulation and function as it relates to the control of Rheb and mTORC1. ..
- Costa Mattioli M, Sossin W, Klann E, Sonenberg N. Translational control of long-lasting synaptic plasticity and memory. Neuron. 2009;61:10-26 pubmed publisher..In this review, we summarize and discuss recent progress in the field and highlight the prospects for better understanding of long-lasting changes in synaptic strength, learning, and memory and implications for neurological diseases. ..
- Toschi A, Lee E, Xu L, Garcia A, Gadir N, Foster D. Regulation of mTORC1 and mTORC2 complex assembly by phosphatidic acid: competition with rapamycin. Mol Cell Biol. 2009;29:1411-20 pubmed publisher..This study also suggests that by suppressing PLD activity, mTORC2 could be targeted therapeutically with rapamycin. ..
- Alliouachene S, Tuttle R, Boumard S, Lapointe T, Berissi S, Germain S, et al. Constitutively active Akt1 expression in mouse pancreas requires S6 kinase 1 for insulinoma formation. J Clin Invest. 2008;118:3629-38 pubmed publisher..Our results therefore identify S6K1 as a critical element for MyrAkt1-induced tumor formation and suggest that it may represent a useful target for anticancer therapy downstream of mTOR. ..
- Bjedov I, Toivonen J, Kerr F, Slack C, Jacobson J, Foley A, et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 2010;11:35-46 pubmed publisher..Rapamycin could increase life span of weak insulin/Igf signaling (IIS) pathway mutants and of flies with life span maximized by dietary restriction, indicating additional mechanisms. ..
- Blagosklonny M. Rapamycin-induced glucose intolerance: hunger or starvation diabetes. Cell Cycle. 2011;10:4217-24 pubmed publisher..If rapamycin is a CR-mimetic, no wonder it may, in certain models, induce "hunger diabetes." But will rapamycin prevent true type II diabetes? Here are some answers. ..
- Magnuson B, Ekim B, Fingar D. Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem J. 2012;441:1-21 pubmed publisher..As dysregulation of this signalling axis contributes to diverse disease states, improved understanding of S6K regulation and function within mTOR signalling networks may enable the development of novel therapeutics. ..
- Jastrzebski K, Hannan K, Tchoubrieva E, Hannan R, Pearson R. Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function. Growth Factors. 2007;25:209-26 pubmed..Finally, we will discuss the impact of S6K signaling and the consequent feedback regulation of the PI3K/Akt pathway on disease processes including cancer. ..
- Buck M, Chojkier M. A ribosomal S-6 kinase-mediated signal to C/EBP-beta is critical for the development of liver fibrosis. PLoS ONE. 2007;2:e1372 pubmed..These data indicate that the RSK-C/EBPbeta phosphorylation pathway is critical for the development of liver fibrosis and suggest a potential therapeutic target. ..
- Zeng X, Kinsella T. Mammalian target of rapamycin and S6 kinase 1 positively regulate 6-thioguanine-induced autophagy. Cancer Res. 2008;68:2384-90 pubmed publisher..Activated Akt is a well-known inhibitor of autophagy. In conclusion, our data indicate that mTOR-S6K1 positively regulates autophagy after MMR processing of 6-TG probably through its negative feedback inhibition of Akt. ..
- Misra U, Pizzo S. Receptor-recognized ??-macroglobulin binds to cell surface-associated GRP78 and activates mTORC1 and mTORC2 signaling in prostate cancer cells. PLoS ONE. 2012;7:e51735 pubmed publisher..Binding of ?(2)M* to prostate cancer cell surface GRP78 upregulates mTORC1 and mTORC2 activation and promotes protein synthesis in the prostate cancer cells. ..
- Lee S, Kim S, Lee J, Park J, Lee G, Kim Y, et al. ATG1, an autophagy regulator, inhibits cell growth by negatively regulating S6 kinase. EMBO Rep. 2007;8:360-5 pubmed..Taken together, our genetic and biochemical results strongly indicate crosstalk between autophagy and cell growth regulation. ..
- Arvisais E, Romanelli A, Hou X, Davis J. AKT-independent phosphorylation of TSC2 and activation of mTOR and ribosomal protein S6 kinase signaling by prostaglandin F2alpha. J Biol Chem. 2006;281:26904-13 pubmed..The translation of proteins under the control of mTOR may have implications for luteal development and regression and offer new strategies for therapeutic intervention in PGF2alpha-target tissues. ..
- Gan B, Melkoumian Z, Wu X, Guan K, Guan J. Identification of FIP200 interaction with the TSC1-TSC2 complex and its role in regulation of cell size control. J Cell Biol. 2005;170:379-89 pubmed..Together, these results suggest a cellular function of FIP200 in the regulation of cell size by interaction with the TSC1-TSC2 complex. ..
- Brugarolas J, Lei K, Hurley R, Manning B, Reiling J, Hafen E, et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 2004;18:2893-904 pubmed..Inhibition of mTOR function by hypoxia is likely to be important for tumor suppression as TSC2-deficient cells maintain abnormally high levels of cell proliferation under hypoxia. ..
- Shah O, Wang Z, Hunter T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol. 2004;14:1650-6 pubmed..Our results suggest that inappropriate activation of the Rheb/mTOR/S6K pathway imposes a negative feedback program to attenuate IRS-dependent processes such as cell survival. ..
- Murakami M, Ichisaka T, Maeda M, Oshiro N, Hara K, Edenhofer F, et al. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol. 2004;24:6710-8 pubmed..These data show that mTOR controls both cell size and proliferation in early mouse embryos and embryonic stem cells. ..
- Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18:1926-45 pubmed..We also summarize the roles of mTOR in the control of cell growth and proliferation, as well as its relevance to cancer and synaptic plasticity. ..
- Pan K, Palter J, Rogers A, Olsen A, Chen D, Lithgow G, et al. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell. 2007;6:111-9 pubmed..Thus, mRNA translation exerts pleiotropic effects on growth, reproduction, stress resistance and lifespan in C. elegans. ..
- Reiling J, Hafen E. The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev. 2004;18:2879-92 pubmed
- Guertin D, Stevens D, Thoreen C, Burds A, Kalaany N, Moffat J, et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell. 2006;11:859-71 pubmed..Thus, mTORC1 function is essential in early development, mLST8 is required only for mTORC2 signaling, and mTORC2 is a necessary component of the Akt-FOXO and PKCalpha pathways. ..
- Harrington L, Findlay G, Gray A, Tolkacheva T, Wigfield S, Rebholz H, et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol. 2004;166:213-23 pubmed..Our results argue that the low malignant potential of tumors arising from TSC1-2 dysfunction may be explained by the failure of TSC mutant cells to activate PI3K and its downstream effectors. ..
- Hinton H, Clarke R, Cantrell D. Antigen receptor regulation of phosphoinositide-dependent kinase 1 pathways during thymocyte development. FEBS Lett. 2006;580:5845-50 pubmed..The present data identifying antigen receptor signaling as a key activator of PDK1 mediated signaling afford a molecular explanation for the important role of this molecule in T cells. ..
- Cota D, Proulx K, Smith K, Kozma S, Thomas G, Woods S, et al. Hypothalamic mTOR signaling regulates food intake. Science. 2006;312:927-30 pubmed..Thus, mTOR is a cellular fuel sensor whose hypothalamic activity is directly tied to the regulation of energy intake. ..
- Dorrello N, Peschiaroli A, Guardavaccaro D, Colburn N, Sherman N, Pagano M. S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science. 2006;314:467-71 pubmed..We propose that regulated degradation of PDCD4 in response to mitogens allows efficient protein synthesis and consequently cell growth. ..
- Bateman J, McNeill H. Temporal control of differentiation by the insulin receptor/tor pathway in Drosophila. Cell. 2004;119:87-96 pubmed..These data suggest that intricate developmental decisions are coordinated with nutritional status and tissue growth by the InR signaling pathway. ..
- Wang X, Beugnet A, Murakami M, Yamanaka S, Proud C. Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins. Mol Cell Biol. 2005;25:2558-72 pubmed..These data have important implications for understanding signaling downstream of mTOR and the development of new strategies to impair mTOR signaling. ..
- Holz M, Ballif B, Gygi S, Blenis J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell. 2005;123:569-80 pubmed..Thus, the eIF3 preinitiation complex acts as a scaffold to coordinate a dynamic sequence of events in response to stimuli that promote efficient protein synthesis. ..
- Scott R, Schuldiner O, Neufeld T. Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev Cell. 2004;7:167-78 pubmed..Thus, in cells lacking TOR, autophagy plays a protective role that is dominant over its potential role as a growth suppressor. ..
- Findlay G, Yan L, Procter J, Mieulet V, Lamb R. A MAP4 kinase related to Ste20 is a nutrient-sensitive regulator of mTOR signalling. Biochem J. 2007;403:13-20 pubmed..Our results therefore suggest a model whereby nutrients signal to mTORC1 via activation of MAP4K3. ..
- Hansen M, Taubert S, Crawford D, Libina N, Lee S, Kenyon C. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell. 2007;6:95-110 pubmed..Our findings link TOR, but not sir-2.1, to the longevity response induced by dietary restriction (DR) in C. elegans, and they suggest that neither TOR inhibition nor DR extends lifespan simply by reducing protein synthesis. ..
- Dann S, Selvaraj A, Thomas G. mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol Med. 2007;13:252-9 pubmed..Thus, to orchestrate the control of homeostatic responses, mTOR Complex1 must integrate signals from distinct cues. Here, we review recent findings concerning the regulation and pathophysiology associated with mTOR Complex1 and S6K1. ..
- Blouet C, Schwartz G. Brainstem nutrient sensing in the nucleus of the solitary tract inhibits feeding. Cell Metab. 2012;16:579-87 pubmed
- Mackenzie M, Hamilton D, Murray J, Baar K. mVps34 is activated by an acute bout of resistance exercise. Biochem Soc Trans. 2007;35:1314-6 pubmed
- Carr T, DiGiovanni J, Lynch C, Shantz L. Inhibition of mTOR suppresses UVB-induced keratinocyte proliferation and survival. Cancer Prev Res (Phila). 2012;5:1394-404 pubmed publisher..Our findings underscore the importance of both mTOR complexes in mediating UVB-induced signaling in keratinocytes and provide new insight into the pathogenesis of skin cancer. ..
- Bielohuby M, Sisley S, Sandoval D, Herbach N, Zengin A, Fischereder M, et al. Impaired glucose tolerance in rats fed low-carbohydrate, high-fat diets. Am J Physiol Endocrinol Metab. 2013;305:E1059-70 pubmed publisher..Therefore, use of LC-HF diets for weight loss or other therapeutic purposes should be balanced against potentially harmful metabolic side effects. ..
- Hoogeveen Westerveld M, Ekong R, Povey S, Mayer K, Lannoy N, Elmslie F, et al. Functional assessment of TSC2 variants identified in individuals with tuberous sclerosis complex. Hum Mutat. 2013;34:167-75 pubmed publisher..Our data support the notion that different, nonterminating TSC2 mutations can have distinct effects on TSC1-TSC2 function, and therefore, on TSC pathology. ..
- Dey N, Ghosh Choudhury N, Das F, Li X, Venkatesan B, Barnes J, et al. PRAS40 acts as a nodal regulator of high glucose-induced TORC1 activation in glomerular mesangial cell hypertrophy. J Cell Physiol. 2010;225:27-41 pubmed publisher..Thus, our data identify high glucose-induced phosphorylation and inactivation of PRAS40 as a central node for mesangial cell hypertrophy in diabetic nephropathy. ..
- Yin Y, Yao K, Liu Z, Gong M, Ruan Z, Deng D, et al. Supplementing L-leucine to a low-protein diet increases tissue protein synthesis in weanling pigs. Amino Acids. 2010;39:1477-86 pubmed publisher..These novel findings provide a molecular basis for designing effective nutritional means to increase the efficiency of nutrient utilization for protein accretion in neonates. ..
- Moon Z, Wang Y, Aryan N, Mousseau D, Scheid M. Serine 396 of PDK1 is required for maximal PKB activation. Cell Signal. 2008;20:2038-49 pubmed publisher..This study therefore reveals that S396 plays a role in the activation of PKB leading to the regulated phosphorylation of some PKB substrates including FOXO3alpha. ..
- Wu X, He L, Cai Y, Zhang G, He Y, Zhang Z, et al. Induction of autophagy contributes to the myocardial protection of valsartan against ischemia?reperfusion injury. Mol Med Rep. 2013;8:1824-30 pubmed publisher..In conclusion, valsartan preconditioning induced autophagy via the AKT/mTOR/S6K pathway, which contributed to the myocardial protection against I/R injury. ..
- Hiraki Hotokebuchi Y, Yamada Y, Kohashi K, Yamamoto H, Endo M, Setsu N, et al. Alteration of PDGFR?-Akt-mTOR pathway signaling in fibrosarcomatous transformation of dermatofibrosarcoma protuberans. Hum Pathol. 2017;67:60-68 pubmed publisher..This study suggested the association of activation of Akt-mTOR pathway proteins and PDGFR with the progression of DFSP to FS. The Akt-mTOR pathway is thus a potential therapeutic target in imatinib-resistant DFSP/FS. ..